PROJECT SUMMARY/ABSTRACT This application to the Fogarty International Research Scientist Development Award is to support Dr. Patrick Cudahy towards an independent clinical research career under mentorship from scientists in the United States and South Africa. Dr. Cudahy?s research focuses on the epidemiology and outcomes of patients with multidrug- resistant tuberculosis (MDR-TB) and HIV co-infection. He has worked in the region for the over ten years, and full-time for the past 30 months. His research site in the KwaZulu-Natal province of South Africa has a high incidence of MDR-TB and HIV co-infection with high rates of treatment failure and mortality. The proposed research will require developing well characterized longitudinal cohorts and collaborating with in-country laboratory scientists to apply clinical diagnostics and innovative genomic techniques. There are three aims of the proposal: 1) To find markers of tuberculosis treatment response in patients co-infected with HIV and MDR- TB; 2) To describe the impact of within-host complexity of M. tuberculosis infection on MDR-TB treatment outcomes in HIV-coinfected individuals; and 3) To describe the within-host spatial diversity of M. tuberculosis strains within HIV-coinfected individuals dying during treatment for MDR-TB. Dr. Cudahy will enroll participants at the start of MDR-TB therapy and follow them with serial blood and sputum assays for the first 16 weeks of treatment. Through these studies, Dr. Cudahy will advance his training in clinical and basic science research in resource limited settings, acquire analytical and biostatistics skills for clinical and epidemiologic research, and develop expertise in bioinformatics. He will conduct the project under the guidance of his U.S. mentor, Dr. Theodore Cohen, Associate Professor of Epidemiology of Microbial Diseases at the Yale School of Public Health, whose research focuses on the emergence and spread of drug-resistant M. tuberculosis. He has previously mentored two trainees that have received K-series awards and 6 postdoctoral fellows who have successfully competed for tenure-track faculty positions. Dr. Cudahy?s South African mentor is Dr. Douglas Wilson, a clinician and accomplished researcher who has over 15 years? experience in conducting both longitudinal clinical and epidemiological studies of tuberculosis and HIV in South Africa. Additionally, Dr. David Engelthaler, Co-Director and Associate Professor of the Pathogen and Microbiome Division at TGen North has developed novel genotyping techniques for genomic epidemiology and will provide expertise in next-generation sequencing tools. The results of this research will form the basis for an R01 application to evaluate interventional strategies based on markers of treatment response and evidence of multiple strain M. tuberculosis infection. Ultimately, this work will produce a better understanding of MDR-TB and HIV co- infection and contribute to the design of interventions that can improve patient outcomes.